RXYLT1 (also known as TMEM5) is a Golgi-localized UDP-D-xylose:ribitol-5-phosphate beta1,4-xylosyltransferase that catalyzes transfer of xylose to ribitol 5-phosphate, forming the Xylβ1-4Rbo5P linkage on O-mannosyl glycans 1. This enzyme participates in biosynthesis of the phosphorylated O-mannosyl trisaccharide on alpha-dystroglycan (DAG1), a critical modification required for high-affinity binding to laminin G-domain-containing extracellular matrix proteins 23. RXYLT1 functions as part of an enzymatic complex with fukutin and FKRP to facilitate prompt glycosylation of dystroglycan 4. RXYLT1 mutations cause severe congenital dystroglycanopathies, most notably Walker-Warburg syndrome (WWS), accounting for approximately 9% of genetically confirmed cases 5. Pathogenic variants have also been identified in cobblestone lissencephaly, muscle-eye-brain disease, and other forms of dystroglycanopathy 6. Clinical presentations include macrocephaly, cobblestone cortical dysplasia, hydrocephalus, ocular abnormalities (microphthalmia, persistent hyaloidal arteries), and muscular dystrophy with elevated creatine kinase levels 78. Notably, identical RXYLT1 genotypes can produce variable phenotypic severity between siblings 5, suggesting genetic modifiers influence disease manifestation.